Asthma is a complex disease involving the concerted actions of multiple inflammatory and immune cells, spasmogens, inflammatory mediators, cytokines and growth factors. In recent practice there have been four major classes of compounds used in the treatment of asthma, namely bronchodilators (e.g., .beta.-adrenoceptor agonists), anti-inflammatory agents (e.g., corticosteroids), prophylactic anti-allergic agents (e.g., cromolyn sodium) and xanthines (e.g., theophylline) which appear to possess both bronchodilating and anti-inflammatory activity.
Theophylline has been a preferred drug of first choice in the treatment of asthma. Although it has been touted for its direct bronchodilatory action, theophylline's therapeutic value is now believed to also stem from anti-inflammatory activity. Its mechanism of action remains unclear. However, it is believed that several of its cellular activities are important in its activity as an anti-asthmatic, including cyclic nucleotide phosphodiesterase inhibition, adenosine receptor antagonism, stimulation of catecholamine release, and its ability to increase the number and activity of suppressor T-lymphocytes. While all of these may actually contribute to its activity, only PDE inhibition may account for both the anti-inflammatory and bronchodilatory components. However, theophylline is known to have a narrow therapeutic index and a wide range of untoward side effects which are considered problematic.
Of the activities mentioned above, theophylline's activity in inhibiting cyclic nucleotide phosphodiesterase has received considerable attention recently. Cyclic nucleotide phosphodiesterases (PDEs) have received considerable attention as molecular targets for anti-asthmatic agents. Cyclic 3',5'-adenosine monophosphate (cAMP) and cyclic 3',5'-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids. At least two therapeutically important effects could result from phosphodiesterase inhibition, and the consequent rise in intracellular adenosine 3',5'-monophosphate (cAMP) or guanosine 3',5'-monophosphate (cGMP) in key cells in the pathophysiology of asthma. These are smooth muscle relaxation (resulting in bronchodilation) and anti-inflammatory activity.
It has become known that there are multiple, distinct PDE isoenzymes which differ in their cellular distribution. A variety of inhibitors possessing a marked degree of selectivity for one isoenzyme or the other have been synthesized.
The structure-activity relationships (SAR) of isozyme-selective inhibitors has been discussed in detail, e.g., in the article of Theodore J. Torphy, et al., "Novel Phosphodiesterase Inhibitors For The Therapy Of Asthma", Drug News & Prospectives, 6(4) May 1993, pages 203-214. The PDE enzymes can be grouped into five families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. PDE I is stimulated by Ca.sup.2+ /calmodulin. PDE II is cGMP-stimulated, and is found in the heart and adrenals. PDE III is cGMP-inhibited, and inhibition of this enzyme creates positive inotropic activity. PDE IV is cAMP specific, and its inhibition causes airway relaxation, antiinflammatory and antidepressant activity. PDE V appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE V inhibitors may have cardiovascular activity.
While there are compounds derived from numerous structure activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited. Analogues of rolipram, which has the following structural formula (A): ##STR2##
and of RO-20-1724, which has the following structural formula (B): ##STR3##
have been studied.
U.S. Pat. No. 4,308,278 discloses compounds of the formula (C) ##STR4##
wherein R.sub.1 is (C.sub.3 -C.sub.6) cycloalkyl or benzyl; each of R.sub.2 and R.sub.3 is hydrogen or (C.sub.1 -C.sub.4) alkyl; R.sub.4 is R.sub.2 or alkoxycarbonyl; and R.sub.5 is hydrogen or alkoxycarbonyl.
Compounds of Formula (D) are disclosed in U.S. Pat. No. 3,636,039. These compounds are benzylimidazolidinones which act as hypertensive agents. ##STR5##
Substituents R.sub.1 -R.sub.4 in Formula D represent a variety of groups, including hydrogen and lower alkyl.
PCT publication WO 87/06576 discloses antidepressants of Formula E: ##STR6##
wherein R.sub.1 is a polycycloalkyl group having from 7 to 11 carbon atoms; R.sub.2 is methyl or ethyl; X is O or NH; and Y comprises of a mono-or bicyclic heterocyclic group with optional substituents.
Rolipram, which was initially studied because of its activity as an anti-depressant, has been shown to selectively inhibit the PDE IV enzyme and this compound has since become a standard agent in the classification of PDE enzyme subtypes. There appears to be considerable therapeutic potential for PDE IV inhibitors. Early work focused on depression as a CNS therapeutic endpoint and on inflammation, and has subsequently been extended to include related diseases such as dementia and asthma. In-vitro, rolipram, RO20-1724 and other PDE IV inhibitors have been shown to inhibit (1) mediator synthesis/release in mast cells, basophils, monocytes and eosinophils; (2) respiratory burst, chemotaxis and degranulation in neutrophils and eosinophils; and (3) mitogen-dependent growth and differentiation in lymphocytes (The PDE IV Family Of Calcium-Phosphodiesterases Enzymes, John A. Lowe, III, et al., Drugs of the Future 1992, 17(9):799-807).
PDE IV is present in all the major inflammatory cells in asthma including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down regulation of inflammatory cell activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. These are undesirable side effects for an anti-inflammatory agent. Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation. With this well-known distinction between PDE isozymes, the opportunity for concomitant anti-inflammation and bronchodilation without many of the side effects associated with theophylline therapy is apparent. The increased incidence of morbidity and mortality due to asthma in many Western countries over the last decade has focused the clinical emphasis on the inflammatory nature of this disease and the benefit of inhaled steroids. Development of an agent that possesses both bronchodilatory and antiinflammatory properties would be most advantageous.
It appears that selective PDE IV inhibitors should be more effective with fewer side effects than theophylline. Clinical support has been shown for this hypothesis. Furthermore, it would be desirable to provide PDE IV inhibitors which are more potent and selective than rolipram and therefore have a lower IC.sub.50 so as to reduce the amount of the agent required to effect PDE IV inhibition.
In recent years, several different compounds have been suggested as possible therapeutic compositions which achieve the desired PDE IV inhibition without the side effects alluded to above. However, these efforts have been chiefly directed to developing non-specific derivatives of particular classes of compounds, i.e. rolipram analogs, benzoxazoles, adenines, thioxanthines, etc. These efforts, however, have resulted in a myriad of compounds having a wide range of PDE IV IC.sub.50 's. Often, the general formulas disclosed yield several compounds which have poor levels of PDE IV inhibition and/or lack sufficient specificity. Consequently, these efforts often provide no assurance that any particular derivative within the formula will have the desired combination of high PDE IV inhibition and selectivity.
Additional thioxanthine compounds are known to the art. However, although some have been suggested to be useful for treating, e.g., asthma, the specific anti-PDE IV activity of these compounds has not been determined. For example, French Pharmaceutical Patent No. 835 818 (188M), issued on Aug. 12, 1960 to May & Baker, Ltd. discloses the synthesis of the disubstituted thioxanthines 3-butyl-1-methyl-6-thioxanthine and 3-isobutyl-1-methyl-6-thioxanthine for bronchial or coronary artery dilation without disclosing any PDE IV inhibitory effects. French Pharmaceutical Patent No. 835 811 (188M) also discloses trisubstituted 6-thioxanthines (Formula I) having at the 1 and 3 positions an alcohol or alkyl (C.sub.1-6), straight or branched and H or an alcohol (C.sub.1-6) at the 8 position.
Woolridge et al., 1962, J. Chem. Soc. Annex IV:1863-1868 discloses the synthesis of disubstituted 6-thioxanthines: 1,3 and 3,7-disubstituted 6-thioxanthines for bronchial or coronary dilation as well as 1,3,8 lower tri-alkyl substituted 6-thioxanthines where the alkyl groups are methyl or ethyl. PDE IV activity was uncharacterized.
Armitage et al., 1961, Brit. J. Pharm. 17:196-207, disclose trisubstituted 6-thioxanthines having bronchial and coronary dilator activity. The 1,3,8-trisubstituted 6-thioxanthines disclosed by Armitage are 1,3,8-trimethyl-6-thioxanthine and 1,3-dimethyl-8-ethyl-6-thioxanthine.
Some trisubstituted xanthine derivatives having diuretic, renal protective and vasodilator properties are disclosed by U.S. Pat. No. 5,068,236, issued to Suzuki et al. on Nov. 26, 1991. Suzuki et al. disclose xanthines, including trisubstituted xanthines having a lower alkyl independently at positions 1 and 3 and a --CH.sub.2 --(R.sup.4)R.sup.5 group at the 8 position, wherein R.sup.4 and R.sup.5 are independently substituted or unsubstituted alicyclic alkyl or substituted or unsubstituted aryl. The exemplified trisubstituted compounds having bronchial and coronary dilator activity are not characterized as to PDE IV activity.
Therefore, there remains a continuing need to find new thioxanthine compounds having more selective and improved PDE IV inhibitory activity.
Commonly owned U.S. Pat. No. 4,925,847, issued May 15, 1990, to Hofer, which is hereby incorporated by reference in its entirety, discloses 3,8-alkyl-disubstituted 6-thioxanthines having PDE IV inhibition.
Commonly owned PCT Application No. WO 96/18399, which is hereby incorporated by reference in its entirety, discloses and claims aryl thioxanthines having PDE IV inhibitory activity of formulas I or II, as set forth below: ##STR7##
wherein Q.sub.3, Q.sub.6a, Q.sub.6b are independently a bond, C.sub.1-8 alkylene, C.sub.2-8 alkenylene and C.sub.2-8 alkynylene, and PA1 R.sub.3, R.sub.6a, R.sub.6b and R.sub.8 are independently hydrogen, aryl or heteroaryl, optionally substituted by halogen, hydroxy, alkoxy, nitro, cyano and carboxy, provided that PA1 Q.sub.3 R.sub.3 is not hydrogen or methyl in formulas (I) or (II); PA1 and at least one of R.sup.3 and R.sup.8 is aryl or heteroaryl. PA1 wherein: PA1 R.sub.1, R.sub.3 and R.sub.8 are independently selected from alkyl, aryl and aralkyl moieties; PA1 R.sub.2 and R.sub.6 are independently S or O; PA1 with the exception that R.sub.2 and R.sub.6 are not both O. PA1 R.sup.1 is a C.sub.2-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl or cycloalkynyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl is optionally substituted with hydroxy, C.sub.1-5 alkoxy, C.sub.3-5 cycloalkoxy, halogen, oxo, carbamido, hydroxycarbamido, oximido, C.sub.1-5 alkyloximido, C.sub.3-5 cycloalkyloximido, C.sub.1-5 acyloximido or C.sub.3-5 cycloacyloximido; PA1 Q is methylene or ethylene; PA1 R.sup.3 is aryl or heteroaryl wherein said aryl or heteroaryl has one to three substituents selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, cycloalkynyl, C.sub.3-5 alkylene, C.sub.3-5 cycloalkylene, haloC.sub.1-6 alkyl, haloC.sub.1-6 cycloalkyl, hydroxy, C.sub.1-5 alkoxy, C.sub.3-5 cycloalkoxy, C.sub.1-2 alkylenedioxy, C.sub.1-6 acyl, C.sub.3-6 cycloacyl, C.sub.1-6 acyloxy, C.sub.3-6 cycloacyloxy, halogen, nitro or cyano; PA1 R.sup.8 is C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, or C.sub.3-5 cycloalkyl, optionally substituted by hydroxy, C.sub.1-5 alkoxy, C.sub.3-5 cycloalkoxy, C.sub.1-5 acyloxy, benzyloxy, C.sub.3-5 cycloacyloxy or halogen. PA1 R.sup.1 is a C.sub.2-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl or cycloalkynyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl is optionally substituted with hydroxy, C.sub.1-5 alkoxy, C.sub.3-5 cycloalkoxy, halogen, oxo, carbamido, hydroxycarbamido, oximido, C.sub.1-5 alkyloximido, C.sub.3-5 cycloalkyloximido, C.sub.1-5 acyloximido or C.sub.3-5 cycloacyloximido; PA1 Q is methylene or ethylene; PA1 R.sup.3 is aryl or heteroaryl wherein said aryl or heteroaryl has one to three substituents selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, cycloalkynyl, C.sub.3-5 alkylene, C.sub.3-5 cycloalkylene, haloC.sub.1-6 alkyl, haloC.sub.1-6 cycloalkyl, hydroxy, C.sub.1-5 alkoxy, C.sub.3-5 cycloalkoxy, C.sub.1-2 alkylenedioxy, C.sub.1-6 acyl, C.sub.3-6 cycloacyl, C.sub.1-6 acyloxy, C.sub.3-6 cycloacyloxy, halogen, nitro or cyano; PA1 R.sup.8 is C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, or C.sub.3-5 cycloalkyl, optionally substituted by hydroxy, C.sub.1-5 alkyloxy, C.sub.3-5 cycloalkyloxy, C.sub.1-5 acyloxy, benzyloxy, C.sub.3-5 cycloacyloxy or halogen.
Commonly owned PCT Application No. WO 96/18400, which is hereby incorporated by reference in its entirety, discloses and claims Trisubstituted Thioxanthines having PDE IV inhibitory activity of formula I as set forth below: ##STR8##
It has now been discovered that appropriately substituted 3-(Arylalkyl)Xanthines, which are selected precursors of compounds disclosed in WO 96/18400, show highly increased PDE IV and PDE V inhibitory activity over known xanthine derivatives, including xanthine derivatives described in the aforementioned British Journal of Pharmacology. The compounds of the invention also show increased inhibition of lymphocyte proliferation over the prior art.